(a) Field of the Invention
This invention relates to an improved process for preparing apomorphine and its derivatives by rearrangement of the corresponding morphine derivative.
(B) Description of the Prior Art
The use of a variety of acids to effect the morphine/apomorphine type rearrangement by heating the corresponding morphine derivative with the acid is known, including concentrated aqueous zinc chloride solutions [Mayer, Ber. 4, 121-128 (1871)--apomorphine (no yield given); Matthiessen et al., Ann. 158, 131-135 (1871)--apocodeine (no yield given); German Pat. No. 489,185, Frdl. 16 (II), 2485-2486 (1927-1929)--apocodeine (25% yield) and apomorphine ethyl ether (2% yield)], concentrated hydrochloric acid [Matthiessen et al., Proc. Roy. Soc. (London) B17, 455-462 (1869)--apomorphine (no yield given)], anhydrous oxalic acid [Knorr et al., Ber. 40, 3355-3358 (1907)--apocodeine (no yield given); Folkers, J. Am. Chem. Soc. 58, 1814-1815 (1936)--apocodeine (12.8% yield); Corrodi et al., Helv. Chim. Acta. 38, 2038-2043 (1955)--norapocodeine (13% yield)], 85% or 90% phosphoric acid with current of anhydrous hydrogen chloride passed through mixture [Oparina, Khim. Farm. Prom. 15, 18-19 (1934); U.S.S.R. Pat. No. 40,981 (Jan. 31, 1935); C.A. 30, 7285 (1936)--apomorphine (40-42%); Hensiak, J. Med. Chem. 8, 557-559 (1965)--N-allylnorapomorphine (46% yield)], 85% phosphoric acid with current of nitrogen passed through mixture [Koch et al., J. Med. Chem. 11, 977-981 (1968)--apocodeine (20% yield), norapomorphine (13% yield), N-ethylnorapomorphine (36% yield), N-propylnorapomorphine (37% yield), N-propargylnorapomorphine (20% yield), N-cyclopropylmethylnorapomorphine (33% yield), N-benzylnorapomorphine (37% yield), N-phenethylnorapomorphine (16% yield)], aqueous glacial phosphoric acid [(HPO.sub.3).sub.n -See Merck Index-Eighth Edition, page 824] [Wright, J. Chem. Soc. 25, 652-657 (1872)--apomorphine (0.6% yield)] and glacial phosphoric acid [Small et al., J. Org. Chem. 5, 334-349 (1940)--apocodeine (30% yield)].